Protein kinases are important in the transmission of biochemical signals, which initiate cell replication. Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in adverse conditions including cancer [Traxler, P. M., Exp. Opin. Ther. Patents, 8, 1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998)], restenosis [Mattsson, E., Trends Cardiovas. Med. 5, 200 (1995); Shaw, Trends Pharmacol. Sci. 16, 401 (1995) ], atherosclerosis [Raines, E. W., Bioessays, 18, 271 (1996)], angiogenesis [Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995)] and osteoporosis [Boyce, J. Clin. Invest., 90,1622 (1992)]. Compounds capable of inhibiting the activity of receptor tyrosine kinases are known to be useful in the treatment of cancers, including but not limited to for example, non-small cell lung cancer (NSCLC), breast cancer, polycystic kidney disease, colonic polyps, and stroke in mammals. A specific kinase inhibitor is (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide, also known as neratinib. Nerartinib is a weak base having low bioavailability and low solubility in both water and alcohol.
Neratinib maleate particles exhibit very high surface free energy, (work of cohesion=45.62 mN/m). This property renders the primary particles very cohesive and prone to aggregation as described by B. Janczuk and T. Bialopiotrowicz, “Surface Free-Energy Components of Liquids and Low Energy Solids and Contact Angles,” in J. Colloid Interf. Sci. 127 (1989), p. 189-204; W. R. Good, “A Comparison of Contact Angle Interpretations,” in J. Colloid Interf. Sci. 44 (1973), p. 63; M. D. Lechner (Ed.), Landolt Börnstein, New Series, Vol. IV/16, “Surface Tension of Pure Liquids and Binary Liquid Mixture,” Springer Verlag, 1998; and J. J. Jasper, “The Surface Tension of Pure Liquid Compounds,” in J. Phys. Chem. Ref. Data, Vol. 1, No. 4, 1972, p. 859. As a consequence of cohesiveness, neratinib maleate powder does not lend itself easily to pharmaceutical operations such as mixing, flow or fluidization especially when it constitutes a high proportion in a composition. Due to these limitations, it was not possible to develop a neratinib maleate formulation comprising a capsule or tablet of higher strength employing a direct compression or roller compaction processes successfully. A formulation using a conventional wet granulation method led to chemical degradation and stability issues.